Xenogeneic islets could provide an unlimited source of tissue for the treatment of diabetes, and could in theory be transplanted repeatedly in a recipient. However, little is known on the consequences of islet re-transplantation in a recipient who has rejected a first graft. In this study, we investigated the functional consequence of xeno islet re-transplantation in mice sensitized with islets from different species. Sprague-Dawley (SD)-rat islets transplanted in sensitized C57/Bl6 mice that rejected either SD- or Lewis-rat islets underwent accelerated rejection. However, accelerated rejection was not found in mice sensitized with pig or human islets, suggesting that accelerated rejection was species specific. Immunohistochemistry showed increased binding of antibodies and accelerated leucocyte infiltration on re-grafted islets in sensitized mice. In situ apoptosis detection indicated that islet cell apoptosis was correlated with the time of leucocyte infiltration, but not with the time of antibody binding. In vitro experiments with cultured islet cells showed that although antibody binding was increased after incubation with sensitized mouse serum, islet cell cytotoxicity was not increased, suggesting that humoral immunity did not play a direct role in islet destruction. These results indicate that there is a cell-mediated, species-specific accelerated rejection after re-transplantation of xenogeneic islets.